Cholera is an acute bacterial, intestinal infection caused by consuming food or water contaminated with the bacteria Vibrio cholera. Despite all the major advances in research, the condition still remains a challenge to the modern medical world. Although the disease may be asymptomatic or mild, severe cholera can cause dehydration, nausea, vomiting, and death within hours of onset. In approximately 50 countries, cholera is endemic in most countries but can cause epidemics at times. According to the World Health Organization, 1.4 to 4.3 million cases are reported each year. The disease has a very rare occurrence in developed, industrialized countries such as the United States. Though rare in industrialized countries, other developing countries located in the Caribbean, Africa, Asia, and Africa, who have trouble with overcrowding, famine, poverty, and primitive water systems, have been impacted with the most epidemics. In most cases, the individual may be asymptomatic all the while infecting others. After few hours or days of being asymptomatic, most individuals will experience symptoms of water diarrhea, nausea, vomiting, and severe dehydration. If left untreated, the individual can go into a state of shock and eventually death. V cholerae O1 cause clinical disease by producing an cholera toxin. This toxin is a protein molecule composed of 5 B subunits and 2 A subunits, which are connected by a disulfide bond. The B subunits are responsible for binding to a gangliosde receptor located on the surface of the cells that line the small intestine.The activation of the A1 subunit by adenylate cyclase is responsible for the net increase in cyclic adenosine monophosphate. cAMP blocks the absorption of sodium and chloride and promotes the secretion of chloride and water. The result is watery diarrhea, which leads to excessive water loss. Figure 1. A colony of Vibrio cholera.
Figur Figure 2. The interaction of the cholera toxin with an epithelial cell of the small intestine.
References:
Antibi
otic Treatment. Centers for Disease Control and
Prevention, (accessed Feb 4, 2016).
Cholera. World Health Organization, (accessed Feb 4, 2016).
Doxycycline - FDA prescribing information, side effects and uses. Doxycycline - FDA prescribing
information, side effects and uses, (accessed Feb 4, 2016).
Doxycycline. DrugBank, (accessed Feb 4, 2016).
He, K.; Ravindran, M. S.; Tsai, B. A Bacterial Toxin and a Nonenveloped Virus Hijack ER-to-
Cytosol Membrane Translocation Pathways to Cause Disease. Critical Reviews in Biochemistry
and Molecular Biology. 2015, 50, 477–488.
InterPro. Guanine nucleotide binding protein (G-protein), alpha subunit (IPR001019) < < EMBL-
EBI, (accessed Feb 4, 2016).
Muanprasat, C.; Chatsudthipong, V. Cholera: Pathophysiology and Emerging Therapeutic Targets.
Future Medicinal Chemistry. 2013, 5, 781–798.
Seas, C.; Gotuzzo, E. Vibrio Cholerae (Cholera). antimicrobe.
The target is the 30S ribosomal protein S12 of the V cholera O1. By binding to the ribosome, there is an inhibition of protein synthesis due to the inability of aminoacyl tRNA of attaching to the ribosome at the A site.
Size: molecular weight of the protein
13,693 Daltons
Location:
The protein is found on the 30S ribosomal unit of V. cholera.
Function in a normal cell:
The 30S ribosomal protein S12 helps bind the aminoacyl tRNA to the 30S ribosome which leads to the translation of other proteins.
Drug Information:
Doxycycline is inhibits the bacterial proteins synthesis by passing the lipid bilayer of bacteria[3]. After entrance, doxycycline binds to the 30 S ribosomal subunits and blocks the bind of aminoacyl rRNA to the mRNA and therefore inhibits the bacterial protein synthesis[3]. It does interact by binding to the alpha subunits of the G proteins but instead decreases the production of cholera toxins[2].
Schematic figure of drug: Figure 3. The chemical structure of doxycycline
Formula: C22 H24 N2 O8
Molecular weight: 444.43 g/mol
CAS Number: 564-25-0
Delivery method: Oral administration
Side effects: Possible side effects of nausea, glossitis, dysphagia, discoloration of teeth, skin photosensitivity, anaphylactic shock and vomiting. In pregnant women, doxycycline could cause stain developing teeth and affect the bone growth of the fetus
Other names: Naphthacenecarboxamide, 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a- pentahydroxy-6-methyl-1,11-dioxo- (6CI,8CI) and 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro- 3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide and Dotur and Vibramycine[3]
Maker or company: Lupin Limited for Lupin Pharmaceuticals
Is it patented? Not patented
Clinical Trials Info: The antibiotic use of doxycycline leads to reduce volume of stool output by 8-92%, duration of diarrhea by 0-56%, and duration of positive bacterial culture by 26-83%[2]
Origin: Its effectiveness derives from being a descendant of chlortetracycline and terramycin. Both were natural products and were modified to form tetracycline, the first semi-synthetic antibiotic. Afterwards, Charlie Stephens at Pfizer created doxycycline which had improved stability and pharmacological efficacy. Alternatives to this drug:
There have been several clinical trials comparing different antibiotics to find which one is most effective. Many of these trials have compared doxycycline to norfloxacin, ciprofloxacin, erythromycin, tetracyclin, furazolidone, and other antibiotics, but the most effective and less expensive.
Miscellaneous: Although doxycycline has been effective in shortening the duration of dehydration, there are still high rates of mortality in countries that have experience large cholera outbreaks and in regions that have limited access to medications. Use of antibiotics also causes mutated strains of Vibrio cholera to become resistant. There has been ongoing research to developing therapeutic drugs that inhibit specifics targets of cholera. These drugs could target the bacterial virulence and motility of the bacteria.
Other uses: can this drug be used to treat other diseases/conditions? Doxycycline has also been used to treat respiratory tract infections cuase by Mycoplasma pneumonia, Haemophilus influenza, Sterptococccus pneumonia, Legionella spp and is also used for prophylaxis of malaria[3]. It is also used as an alternative to treating the plague, tetanus, and Campylobacter fetus.
Disease/Drug of interest: Cholera/Doxycycline
Motivation and Background:
Cholera is an acute bacterial, intestinal infection caused by consuming food or water contaminated with the bacteria Vibrio cholera. Despite all the major advances in research, the condition still remains a challenge to the modern medical world. Although the disease may be asymptomatic or mild, severe cholera can cause dehydration, nausea, vomiting, and death within hours of onset. In approximately 50 countries, cholera is endemic in most countries but can cause epidemics at times. According to the World Health Organization, 1.4 to 4.3 million cases are reported each year. The disease has a very rare occurrence in developed, industrialized countries such as the United States. Though rare in industrialized countries, other developing countries located in the Caribbean, Africa, Asia, and Africa, who have trouble with overcrowding, famine, poverty, and primitive water systems, have been impacted with the most epidemics. In most cases, the individual may be asymptomatic all the while infecting others. After few hours or days of being asymptomatic, most individuals will experience symptoms of water diarrhea, nausea, vomiting, and severe dehydration. If left untreated, the individual can go into a state of shock and eventually death.V cholerae O1 cause clinical disease by producing an cholera toxin. This toxin is a protein molecule composed of 5 B subunits and 2 A subunits, which are connected by a disulfide bond. The B subunits are responsible for binding to a gangliosde receptor located on the surface of the cells that line the small intestine.The activation of the A1 subunit by adenylate cyclase is responsible for the net increase in cyclic adenosine monophosphate. cAMP blocks the absorption of sodium and chloride and promotes the secretion of chloride and water. The result is watery diarrhea, which leads to excessive water loss.
Figure 1. A colony of Vibrio cholera.
Figur
Figure 2. The interaction of the cholera toxin with an epithelial cell of the small intestine.
References:
information, side effects and uses, (accessed Feb 4, 2016).
Cytosol Membrane Translocation Pathways to Cause Disease. Critical Reviews in Biochemistry
and Molecular Biology. 2015, 50, 477–488.
EBI, (accessed Feb 4, 2016).
Future Medicinal Chemistry. 2013, 5, 781–798.
External links:
http://emedicine.medscape.com/article/962643-overview#a2Target Information:
The target is the 30S ribosomal protein S12 of the V cholera O1. By binding to the ribosome, there is an inhibition of protein synthesis due to the inability of aminoacyl tRNA of attaching to the ribosome at the A site.Size: molecular weight of the protein
13,693 DaltonsLocation:
The protein is found on the 30S ribosomal unit of V. cholera.Function in a normal cell:
The 30S ribosomal protein S12 helps bind the aminoacyl tRNA to the 30S ribosome which leads to the translation of other proteins.Drug Information:
Doxycycline is inhibits the bacterial proteins synthesis by passing the lipid bilayer of bacteria[3]. After entrance, doxycycline binds to the 30 S ribosomal subunits and blocks the bind of aminoacyl rRNA to the mRNA and therefore inhibits the bacterial protein synthesis[3]. It does interact by binding to the alpha subunits of the G proteins but instead decreases the production of cholera toxins[2].Schematic figure of drug:
Figure 3. The chemical structure of doxycycline
Formula:
C22 H24 N2 O8
Molecular weight:
444.43 g/mol
CAS Number:
564-25-0
Delivery method:
Oral administration
Side effects:
Possible side effects of nausea, glossitis, dysphagia, discoloration of teeth, skin photosensitivity, anaphylactic shock and vomiting. In pregnant women, doxycycline could cause stain developing teeth and affect the bone growth of the fetus
Other names:
Naphthacenecarboxamide, 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a- pentahydroxy-6-methyl-1,11-dioxo- (6CI,8CI) and 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro- 3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide and Dotur and Vibramycine[3]
Maker or company:
Lupin Limited for Lupin Pharmaceuticals
Is it patented?
Not patented
Clinical Trials Info:
The antibiotic use of doxycycline leads to reduce volume of stool output by 8-92%, duration of diarrhea by 0-56%, and duration of positive bacterial culture by 26-83%[2]
Origin:
Its effectiveness derives from being a descendant of chlortetracycline and terramycin. Both were natural products and were modified to form tetracycline, the first semi-synthetic antibiotic. Afterwards, Charlie Stephens at Pfizer created doxycycline which had improved stability and pharmacological efficacy.
Alternatives to this drug:
There have been several clinical trials comparing different antibiotics to find which one is most effective. Many of these trials have compared doxycycline to norfloxacin, ciprofloxacin, erythromycin, tetracyclin, furazolidone, and other antibiotics, but the most effective and less expensive.
Miscellaneous:
Although doxycycline has been effective in shortening the duration of dehydration, there are still high rates of mortality in countries that have experience large cholera outbreaks and in regions that have limited access to medications. Use of antibiotics also causes mutated strains of Vibrio cholera to become resistant. There has been ongoing research to developing therapeutic drugs that inhibit specifics targets of cholera. These drugs could target the bacterial virulence and motility of the bacteria.
Other uses: can this drug be used to treat other diseases/conditions?
Doxycycline has also been used to treat respiratory tract infections cuase by Mycoplasma pneumonia, Haemophilus influenza, Sterptococccus pneumonia, Legionella spp and is also used for prophylaxis of malaria[3]. It is also used as an alternative to treating the plague, tetanus, and Campylobacter fetus.